CA1260837A - Antiplaque/antigingivitis composition - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

A composition for inhibiting dental plaque and gingivitis containing an effective plaque- and gingivitis- inhibiting amount of polyvinyl phosphonic acid or salt thereof.

Description

1'~6~83~

AN'I'IPLAQUE/ANTIGINGIVITIS COMPOSITION
'I`his invention relates to non~antibacterial agents and oral compositions useful for promoting human oral hygiene, and to a method for treatin~, controlling or inllibiting both plaque and gingivitis, ~hich latter is characterized by such symptoms as inflammation, bleeding, recession, and/ors~elling of the gums. Types of gingivitis include afunctional gingivitis, gingivitis marginal and cotton-roll gingivitis.
Gingivitis leads to periodontitis.
'I'he gums are seriously harmed by deposits of dental plaque, a combination of minerals and bacteria ~ound in the mouth. Tlle bacteria associated with plaque can secrete enzymes and endotoxins which can irritate the gums and cause an inflammatory gingivitis. As the gums become increasingly irritated by this process they have a tendency to bleed, lose their toughness and resiliency, and separate Erom the teeth, leaving periodontal pockets in which debris, secretions, more bacteria and toxlns further accumulate. It is aLso possible for food to accumulate in thcs~ pockets, the*eby providing nourishment Eor increased growth o~ bact~3ria and production o endotoxins and destructive enzymes.
'Actinomyces viscosus, a gram positive rod, has been identified as implicated in the etiology of gingivitis loeche et al "Bacteriology of human experimental gingivitis: effects of plaque and gingivitis sores,"
Infection and Immunity 21, 830-839 (1978). This organism attaches to tooth surfaces to form the dental plaque.
A multitude of materials have been prev~ously proposed and employed for controlling plaque and gingivitis, but none have been entirely satisfactory. For example, some of such materials have been found to be unstabl~ in the presence o the anionic surface active age-nts generally present in conventional oral preparations~ A number of such materials such as the cationic quaternary ammonium agents exert an anti-ha,cterial function ~'hich undesirahly tends to disrupt or destroy the normal microflora of the mouth and/or the digestive system,

-2- ~26~837 62301-1300 U.s. 3,l~ C3 issucd ~cbru~ry ~5, l~ to Lco Sl~ ovsky Dnd assignce in comlnon with thc inst~nt apl~lication proposcs, ~Inong a number of other watcr soluble polyelec-trolytes, the use of polyvinyl phosphonic ~cid (Vl'A polymer) or salts thercof for complexing cDlciuln and inhibiting oral cnlculus, but the sole in vivo test described therein involvcd thc supllying of drinking water containing a hydrolyzed copolymer of ethylene and ~alcic ~nhydride for ad libitum drinkin~ by rats for a period of five days. ~lis test is in the nature of a stoichiometric complcxation of calcium and is unrelated to the threshhold effect occurring in actllal or~l use involving trentlnent of dental surFaces l to

3 times substantially dDily for at least 2 weeks or lifetime. When subjected to such an actual use test, polyvinyl phosphonic acid failed to significantly inhibit oral calculus.
U.S. 4,342,~57 issued August 3, 1982 to Abdul Gaffar, discloses and claims antigingivitis compositions containing a vinyl phosphonic acid/vinyl pliosphonyl fluoride copolymer, but a number of scientisl:s, authorities and/or jurisdictions object to administration of fluorinatcd mnterials to humans.
The present invention is based on the discovery that VPA
polymer and its salts interfere with or inhibit the attachment of ~ctinomyces viscosus to saliva coated hydroxyapatite (~P) beads. This is a rclialle indication that the agent ~ould interfere with the attach-ment of the organis~ to tooth surfaces, should reduce plaque, and hence reduce or inllibit gingivitis. Such antigingivitis activity has in fact been corroborated by an in vivo test on ~eagles as more fully discussed below.
~ccordinl~ to th~ present invcntion, there is now provided un anti-~ingiVitiS nrld nnti-pla(lueornl composition for inhibiting dental plaquc and ~ln~ivitis comprising a dentally acccptable oral vehicle and an effcctive pl~luc~ Dnd ~inF~ivitis-inllibiting amount of polyvinyl pllospl~onic ncid or ;ln orally ;Icceptnblc salt thcreof, wherein said : polyvinyl phosphonic acid has a number average molecular weight of about 6,000 to about 8,000.

~3 126(}837 The invention also includes a method of inhibiting human dental plaque and gingivitis comprising applying to the human oral cavity a composition containing a dentally acceptable oral vehicle and an e-f~ective plaque- and gingivitis- inhibiting amount of polyviny] phosphonic acid or an orally acceptable salt thereof.
The VPA polymer used in this invention should prefer-ably have a number average molecular weight (obtained ~rom viscosity or l:ight scattering measurements) of about 6,000 to about 8,000, and may be prepared in known manner by polymerizing vinyl phosphonyl dichloride under substantially anhydrous con-ditions in the prcsence of a free radical catalyst, and then mixing the resulting polymer with water to hydrolytically convert the vinyl phosphonyl dichloride units in the polymer to VPA units. The resulting polymer is in free acid form and may desirably ~e converted to salt :form by treatment with any orally acceptable cation - providing base such as alkali metal (e.g. sodium or potassium), ammonium, Cl 1~ mono-, cli- and tri-substituted atnmonium, ~e.g. alkanol substituted ammonium, such as mono-, di- and tri-ethanolammonium, organic amines, etc.

~6(?~37 It will be understood that the mono- and di- forms of the polymer are the equivalent of the free acid form and that the term "water soluble" applicable to all such forms is inclusive o~ readily water dispersible forms thereof in the usual use concentrat iOllS .
It will also be understood that the VPA polymer may also contain minor proportions, i.e. less than 50 wt.%, preferably less than about 10 wt. %~ more preferably less than about 5 wt. % most preferably less than about 2 wt. %, of units derived from ol;her non-fluorinated ethylenically unsaturated monomers which~ in type and amount, are nontoxic and do not interfere with the desired water soluble and antigingivitis activities of the polymer. Other such monomers may, Eor example, include olefins such as ethylene, propylene, isoprop~lene, butylene and isobutylene, vinyl lower alkyl ethers such as vinyl methyl, ethyl and isobutyl ethers, alpha, beta unsaturated carboxylic acids and their lower alkyl and substituted lower alkyl esters such as acrylic, methacrylic, aconitic, maleic and fumaric acids and their methyl, ethyl, isobutyl and dimethylaminoethyl esters, allyl alcohol and acetate, vinyl and vinylidene halides, vinyl lower alkanoic acid esters such as vinyl acetate and butyrate, acrylamide and methacrylamide and N-lower alkyl and N, N-dilower alkyl ~ substituted derivatives thereof, and the like.
; The concentration of the VPA polymeric antigingivitis agent in oral comlpositions can range widely, typically upwards of about 0.01% by weight with no uE)per limit except as dictated by cost or incompatibility with the vehicle. Generally, concentrations of about 0.01% to about 10.0~ preferably about 0.1% to about 8.0%, more preferably about 0.5% to about 5.0~ by weight are utilized. Oral compositions which in the ordinary ~6~1~37 course of usage could be accidentally ingested preEerably contain concentrations in the lower portions of the foregoing ranges.
In certain highly preferred forms of the invention, the oral composition may be substantially liquid such as mouthwash or rinse. Such preparations generally contain a humectant and the vehicle is typically a water-alcohol mixture.
Generally, the ratio of water to alcohol is in the range o~
from about 1:1 to about 20:1 preEerably from 3:1 to 20:1 and most preferably about 17:3, by weight. The total amount of water-alcohol mixture in this type of preparation is typically in the range of from about 70 to about 99.9% by weight of the preparation. The pH of such liquid and other preparations of the invention is generally in the range of from about ~.5 to about ~ and typically from about 5.5 to 8Ø The pH is preferably in the range of from about 6 to about 8Ø It is noteworthy that the compositions of the invention may be applie~ oral]y at a lower pH without substantially decalcifying dental enamel.
Such liquid oral preparations may also contain a surface active agent and/or a fluorine-providing compound.
In certain other desirable forms of this invention, the oral composition may be substantially solid or pasty in character, such as toothpowder, a dental tablet, a toothpaste or dental cream. The vehicle of such solid or pasty oral preparations cont:ains polishing material. Examples of polishing matericlls are water-inso:luble sodium metaphosphate, potassium metaphosphate, tricalcium phosphate, calcium pyrophosphate, magnesium orthophosphate, trimagnesium phosphate, calcium carbonate, alumina, hydrated alumina, aluminum silicate, zirconium silicates, silica bentonite, and 12~;~83~

mixtures thereof. Preferred polishiny materials include crystalline silica havin~ particle sizes of up to 5 microns a mean particle size of up to 1.1 microns, and a surface area of up to 50,000 cm2/gm., silica gel, complex amorphous alkali metal aluminosilicate, hydrated alumina, dicalcium phosphate.
Alumina, particularly the hydrated alumina sold by Alcoa as C333, which has an alumina content of 64.9% by weight, a silica content of 0.008%, a ferric oxide content of 0.003~, and a moisture content of 0.037~, at 110C., and which has a speciEic gravity of 2.42 and a particle size such that 100% of the particles are less than 50 microns and 84% of the particles are less than 20 microns, is particularly desirable.
When visually clear gels are employed, a polishing agent of colloidal silica, such as those sold under the trademark S~LOID as Syloid 72 and Syloid 7~ or under the trademark SANTOCEL as Santocel 100 and alkali metal aluminosilicate complexes are particularly useful, since they have reEractive indices close to the refractive indices of gelling agent-liquid (including water and/or humectant) systems commonly used in dentifrices.
Many of the so-called "insoluble" polishing materials are anionic in character and also include small amounts of soluble materials. Thus, insoluble sodium metaphosphate may be formed in any suitable manner, as illustrated by Thorpe's Dictionary of Applied Chemistry, Volume 9, fourth Edition, pp.
510-511. The for~ls of insoluble soclium metaphosphate known as Madrell's salt and Kurrol's salt are further examples of suitable materials. These metaphosphate salts exhibit a minute solubility in water, and therefore are commonly referred to as insoluble metaphosphates. There is present therein a minor amount of soluble phosphate material as impurities, usually a 1~6~:)837 few percent such as up to 4% by weight. The amount of soluble phosphate material, which is believed to include a soluble sodium trimetaphosphate in the case oE insoluble metaphosphate, may be reduced by washing wi-th water if desired. The insoluble alkali metal metaphosphate is typically employed in powder form of a particle size such that no more than about 1% of the material is larger than 37 microns.
The polishing material is generally present in amounts ranging from about 10 to about 99~ by w~ight of the oral preparatlon. Preferably, it is present in amounts ranging from about 10 to about 75% in toothpaste, and from about 70 to about 99% in toothpowder.
In the preparation of toothpowders, it is usually sufficient to admix mechanically, e.g., by milling, the various solid ingredients in appropriate quantities and particle sizes.
In pasty oral preparations the above-defined combination of the antigingivitis agent and polishing material should be compatible with the other components of the preparation. Thus, in a toothpaste, the liquid vehicle may comprise water and humectant typically in an amount ranging from about 10 to about 90~ by weight of the preparation.
Glycerine, sorbitol, or polyethylene glycol may also be present as humectants or binders. Particularly advantageous liquid ingredients are polyethylene glycol and polypropylene glycol.
Also advantageous are liquid mixtures of water, glycerine and sorbitol.
In clear gels where the refractive index is an important consideration, about 3-30% by weight of water, 0 to about 80~ by weight of glycerine, and about 20-28~ by weight of sorbitol is preferably employed. A gelling agent, such as natural or synthetic gums or gumlike materials, typically Irish 12bi0837 moss, sodium carboxymethylcellulose, methyl cellulose, hydroxyethyl cellulose, gum tragacanth, polyvinylpyrrolidone, starch, and preferably hydroxypropyl methyl cellulose and the Carbopols* (e.g. 934,9~0 and 941), etcetera is usually present in toothpaste in an amount of up to about 10% by weight, preferably in the range of from about 0.5 to about 5%. In a toothpaste or gel, the liquids and solids are proportioned to form a creamy or gelled mass which is extrudable from a pressurized container or from a collapsible, e.g., aluminum or lead, tube.
The solid or pasty oral preparation which typically has a pH measured on a 20~ slurry of about 4.5 to 9, generally about 5.5 to about 8 and preferably about 6 to about 8.0 may also contain a surface active agent and/or a fluorine-providing compound.
It will be understood that, as is conventional, the oral preparations are to be sold or otherwise distributed in suitable labelled packages. Thus a jar of mouthrinse will have a label describing it, in substance, as a mouthrinse or mouthwash ancl having directions for its use; and a toothpaste will usually be in a collapsible tube, typically aluminum or lined lead, or other squeeze dispenser for metering out the contents, having a label describing it, in substance, as a toothpaste or dental cream.
The oral compositions of this invention may contain a non-soap synthetLc sufficiently water soluble organic anionic or nonionic surfactant in concentrations generally ranging from about 0.05 to about 10, preferably about 0.5 to about 5, weight percent, to promote wetting, detersive and foaming properties.
U.S. Patent No. 4,041,149 discloses such suitable anionic surfactants in column 4, lines 31-38, and such suitable * Trade mark 8 126~837 nonionic surfactants in column 8, lines 30-68 and column 9, lines 1-12.
In certain forms of thls invention a fluorine-providing compound is present in the oral preparation. These compounds may be slightly soluble in wa-ter or may be fully water-soluble. They are characterized by their ability to release fluoride ions in water and by substantial freedom from reaction with other components of the oral preparation. Among these materials are inorganic 1uoride salts, such as soluble alkali metal, alkaline earth metal and heavy metal salts, for example, sodium fluoride, potassium fluoride, ammonium fluoride, Ca fluoride, a copper fluoride such as cuprous fluoricle, zinc fluoride, a tin fluoride such as stannic fluoricle or stannous chlorofluoride, barium Eluoride, sodium fluorsilicate, ammonium fluorosilicate, sodium fluorozirconate, sodium monofluorophosphate, aluminum mono- and di-fluorophosphate, and fluorinated sodium calcium pyrophosphate.
Alkali metal and tin fluorides, such as sodium and stannous fluorides, sodium monofluorophosphate and mixtures thereof, are preferred.
The amount of the fluorine-providing compound is dependant to some extent upon the type of compound, its solubility and the type of oral preparation, but it must be a nontoxic amount. In a solid oral preparation, such as toothpaste or toothpowder, an amount of such compound which releases a maximum of about 1% by weight of the preparation is considered satisfactory. Any suitable minimum amount of such compound may be used~ but it is preferable to employ sufficient compound to release about 0.005 to 1%, and preferably about 0.1% of fluoride ion. Typically, in the cases of alkali metal fluorides and stannous fluoride, this component is present in ~;~60~37 an amount up to about 2~ by weight, based on the weight of the preparatlon, and preferably in the range of about 0.05 to 1~.
In the case of sodium mono-~luorophosphate, the compound may be present in an amount up to 7.6% by weight, more typically about 0.76%.
In a liquid oral preparation such as a mouthwash, the fluorine-providing compound is typically present in an amount sufficient to release up to about 0.13%, preferably about 0.0013 to 0.1% and most preferably about 0.0013% by weight, of ~luoride.
VarLous other materials may be incorporated in the oral preparations of this invention, subject to the above.
Examples are whitening agents, preservatives, silicones, chlorophyll compounds, and ammoniated material such as urea, diammonium phosphate , and mixtures thereof. These adjuvants, where present, are incorporated in the preparations in amounts which c~o not substantially adversely afEect the properties and charact:eristLcs desired.
Any suitable flavouring or sweet:ening material may also be employed, also subject to the above. Examples of suitable flavouring constituents are flavouring oils, e.g., oils of spearmint, peppermint, wintergreen, sassafras, clove, sage, eucalyptus, marjoram, cinnamon, lemon and orange, and methyl salicylate. Suitable sweetening agents include sucrose, lactose, maltose, sorbitol, sodium cyclamate, perillartine, APM
~aspartylphenylalanine, methyl ester) and saccharin. Suitably, flavour and sweetening agents may together comprise from about 0.1 to 5% or more of the preparatic,n.
In the practice of this invention an oral composition according to this invention such as a mouthwash or toothpaste containing the antigingivitis agent in an orally acceptable 3L;26~1~37 vehicle may be prepared by unifying the components in conventional manner, and applied to the gingiva and teeth regularly, substantially daily, e.g. from about 1 to 3 times daily or every second or third day, etc., at a pH of about ~.5 to about 9, generally about 5.5 to about 8.5, preferably about 6 to about 8, preferably for at least two weeks up to eight weeks or more or lifetime.
In the case of chewing gum and other products, the VPA active ingredients can b~ incorporated in any suit~ble manner during the usual manufacture of the product. For example, they can be incorporated in a warm gum base with stirring to distribute the same uniformly therein. They can also be added to the exterior or outer surfaces oE a gum base in order to coat the base. The usual gum bases can be used, representative materials being jelutone, rubber latex, vinylite resins, etc., in addition to other usual materials such as plasticizers or soteners, sugar or other suitable carbohydrates such as glucose, sorbitol, etc.
The following examples are further illustrative of the nature of this invention but it is understood that the invention is not limited thereto. All amounts and proportions referred to herein and in the appended claims are by weight, and temperatures are in degrees C unless otherwise indicated.
The VPA polymer employed in these examples was in the form of disodium salt.

lZ6~837 EXAMPLE I
Adsorption of Sodium Polvvinyl PhosDhonate to Dental Enamel:
The adsorption of the polymer to enamel surfaces was measured in vitro. Human extracted, non-carious and non-filled molar teeth were cleaned by pumicing. They were then polished with a rubber cup and polishing agent. They were mounted onto a rubber stopper via a nichrome wire which was tied through a hole in the roots. A sodium salt of polymer solutions at pH
7.0 were disp~nsed ln polyethylene tubes. The teeth were submerged in the solution at 37C. for 1 hour under a continuous agitation. Special care was taken to avoid the contact of solution wi-th roots of the teeth. After one hour incubation, the teeth were removed and the solutions were analyzed for the amount of polymer left in the solution. The adsorption was calculated by a diEerence between amount initially added minus the amount left after exposing to teeth.
The concentration of the polymer in the solution was assessed by turbidimetric measurements using 5M CaC12 solution at pH 4.5. 1 cc. of CaC12 was added to 1 cc. of the polymer solution. The turbidity of resull:ing colloidal suspension at 500 nanometer proved to be proportional to the polymer concentration ranging from 1 to 8 mgs/ml. A calibration curve was carried out with the known amount of the polymer.

Results:
Conc. of POly-Amt. Left After Tooth Amt. Adsorbed to Na2VPA (mg/ml) Immersion (mg/ml) Teeth tmg/ml) 2 0.4 1.6 3 0.7 2.3

4 1.1 2.9 1.6 3.4 6 2.4 3.6 7 3.3 3.7 The data indicated a significant adsorption of the VPA polymer to enamel surfaces, 12 . .

126~837 EXAMPLE II

Effect of Polymer on the Adsorption of Actinomvces Viscosus T14 on Saliva Coated Hydroxyapatite (HAP) Beads:
80 mgs. of HAP beads were pre-coated with human saliva (blood type A) for 12 hours. The beads were washed and pre-treated with the solution of the polymer at pH 7.0 for 5 minutes. The treated beads were washed with a buffer consisting of 0.05 M KCl lmM P04, lmM CaCl2 and 0.1 mM MgCl2 at pH 6Ø This buffer simulates saliva inorganic constituents.
For the adsorption studies the mixture (1.0 ml) contained 5 x 107 3H thymidine labelled bacteria (Actinomvces viscosus), 30 mg saliva coated beads (S HAP) and the buffer.
The mixture was continuously shaken at room temperature for 2 hours. The beads were allowed to settle for one minute and the supernatant which contained unadsorbed cells was removed. The radioactivity was measured via liquid scintillation counts.
Portions of known H3 labelled cells were counted in a similar manner so that counts per minute may be related to bacterial cell member. Control bacterial suspensions were incubated with S-HAP beads.

Results:

Effects of Pre-Treatina Saliva Coated HAP Beads With PolYvin Phos~honate on Adsor~tion of Bacteria A. Viscosus LY7 S-HAP Cells Adsorbed (X 107) Treatment Per 20 mq S-HAP~ Relative to Buffer Buffered KCl 3.88 + 0.04 100 1% Na2VPA 1.23 + 0.05 32 Polymer 0.1% Na2VPA 3.54 ~ 0.16 91 Polymer 0.01% Na2 VPA 3.55 + 0.09 92 J~26~83~

The results show that a pre-treatment of S-~AP with 1~
polyvinyl phosphonate was significantly effective in inhibiting bacterial attachment.

EXAMPLE III
This study in 20 beagle dogs evaluated the effect of a placebo and a rinse containing 1~ sodium salt of polyvinyl phosphonic acid on plaque/gingivitis for 4 weeks. The dogs were given complete prophylaxis to remove salt and hard dental deposits. A disclosing solution was used to insure the complete removal of dental deposits. The beagles were kept on a soft diet for,4 weeks. Group I (10 dogs) were then treated with the placebo rinse, while Group II was treated with the rinse containing the polymer. The treatment was done l/day/5 days per week by applying 5-6 cc. of the rinse on all dentition. The study was double blind. Neither the evaluator nor the~ people involved ln the treatments knew the assignments of rinses in the respective groups. The plaque and gingivitis was as~;essed via Loe and Silness index (Ac,ta Odontolo~ica Scandinavica, 21:551-555 t1963)).
TABLE III
Results:

Plaque Index/ Gingival Index Mouth Tooth - 4 wks % 4 Wks Post Rinse N Group Post Treatment Change Treatment Change Placebo 10 I 0.99 + 0.23 --- 0.91 + 0.10 ---1% Na 10 II 0.68 + 0.23 -31 0.73 + 0.29 -20 VPA Poly-mer Compared to the placebo rinse, the polyvinyl phosphonate rinse significantly recluced plaque/gingivitis for four weeks.

126Q83~

The ~Eollowing examples of oral (mouthwash and toothpaste) formulations are further illustrative of this invention.
EXAMPLE IV
Wt. Percent Glycerin 10.0 Ethanol 10.0 Pluronic* Fl08* 3.8 Na Saccharin 0.03 Polyvinyl phosphonate 1.0 Flavour 0.22 Water to make lO0.00 * BAS F-Wyandotte block polymer nonionic surfactant containing about 20 wt.% polyoxypropylene chain of about 3251) M.W. and about 80 wt.% polyoxyethylene.

* Trade;mark :, . .. .

126(~837 EX~MPLE V

Wt, Perccnt Clycerin 25.0 Carboxymet~iyl Ce11ulose 1.3 Sodium Benzoate 0.5 Na Saccharin 0.2 Silica 30.0 Sodium Lauryl Su:Lfate l.S
Polyvinyl Phosphonate . 3.0 Water to make 100.0 This invention has been disclosed with respect to preferred embodiments and it will be understood that modifications ~nd variations thereof obvious to those skilled in the art ate to be included within the spirit and purview of this application and the scope of the appended claims.

q -15- .

Claims (6)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. An anti-gingivitis and anti-plaque oral composition for inhibiting Actinomyces viscosus on a dental surface, dental plaque or gingivitis comprising a dentally acceptable oral vehicle and an effective plaque- and gingivitis-inhibiting amount of polyvinyl phosphonic acid or an orally acceptable salt thereof, wherein said polyvinyl phosphonic acid has a number average molecular weight of about 6,000 to about 8,000.

2. A composition according to claim 1 which comprises about 0.01% to about 10% by weight of the polyvinyl phosphonic acid or salt thereof.

3. A composition according to claim 1 which comprises about 0.5% to about 5% by weight of the polyvinyl phosphonic acid or salt thereof.

4. A composition according to claim 1, 2 or 3 which is a mouthwash having a pH of about 4. 5 to about 9, said oral vehicle being an aqueous-alcohol vehicle.

5. A composition according to claim 1, 2 or 3 which is a toothpaste having a pH of about 4.5 to about 9 with a liquid said oral vehicle, and said composition further comprises a gelling agent and a dentally acceptable polishing agent.

6, A process for preparing an anti-gingivitis and anti-plaque oral composition effective for inhibiting Actinomyces viscosus on dental surface, dental plaque or gingivitis which comprises admixing a dentally acceptable oral vehicle and an effective plaque- and gingivitis- inhibiting amount of polyvinyl phosphonic acid or an orally acceptable salt thereof, wherein said polyvinyl phosphonic acid has a number average molecular weight of about 6,000 to 8,000.